In this proposal we will use DNA polymorphisms for the following purposes: 1) Elucidation of the different mutations producing reduce Beta-globin gene expression (Beta-thalassemia) in Chinese and American Blacks. Using the experience from the study of the Beta-thalassemia mutations in Mediterraneans and Asiatic Indians we anticipate that new and different mutations producing Beta-thalassemia will be associated with each different haplotype of polymorphic sites in the Beta-globin gene cluster in Chinese and American Blacks. All the mutations leading to reduced expression of the Beta-globin gene found so far are physically located in the Beta-globin gene itself. We hope to find among other mutations an entirely normal Beta-globin gene associated with reduced expression, providing the first evidence of a regulatory mutation outside of the Beta-globin gene. We also hope to find mutations of the "cap' site as well as the polyadenylation site of the Beta-globin gene which will provide important information for the understanding of the normal gene expression in eukaryotes. 2) Elucidation of the molecular basis of familial hypoparathyroidism (FH). Using clones of the preproparathyroid hormone gene (ppPTH) and DNA polymorphisms in the vicinity of this gene we will try to i) discover whether the defect in FH is associated with the ppPTH genes, and ii) characterize deletion and non-deletion mutants producing reduced expression of this gene. 3) Detect in DNA samples from a large number of unrelated individuals from different ethnic groups, whether the single nucleotide difference between the oncogene from the bladder carcinoma cell lines EJ and T24 and the normal human homologue is indeed a rare mutation related to oncogenicity, or a simple polymorphism not related to any oncogenic effects. The mutation G greater than T in the codon #12 for glycine eliminates a cleavage site for the restriction endonucleases Nae I and Nsp I and is therefore detectable after Southern blotting. The answer to this question determines whether this particular mutation can be used as a "marker" or "risk factor" for the families of individuals affected with bladder carcinoma.